This review is designed and written by Dr. Yu Zheng and her graduate student Qin Qin (Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University).
Inflammation is a physiological or pathological process in which the body responds to stimuli such as infection, tissue stress/dysfunction/injury, and physical stimulation inducement like hypoxia and tries to restore internal homeostasis. And it accompanies the onset and progression of numerous acute and chronic diseases including rheumatoid arthritis, sepsis, pancreatitis, atherosclerosis, ischaemic brain/heart disease etc.. In this process, inflammatory cells are recruited to the lesion and perform various effector functions to eliminate infection or repair injury. Moderate inflammatory response is beneficial. Excessive inflammatory response will lead to severe pathological syndromes manifesting as systemic inflammatory response syndrome (SIRS), cytokine storm (CS), multiple organ failure (MOF) etc., and even threaten the patient's life. Conventional anti-inflammatory drugs including steroids, non-steroids, anti-leukotrienes, pro-inflammatory cytokine inhibitors, anti-inflammatory peptides and small interfering RNAs(siRNA) drugs have certain disadvantages such as non-specific tissue distribution, low bioavailability, and a short half-life, resulting in off-target side effects and limited efficacy in disease control. To address these issues, nanoparticles have emerged as a novel therapeutic paradigm in this field. These drug-delivery vectors targeting inflammation mainly utilize the disparity in inflammatory microenvironment between inflamed tissue and normal tissue to achieve the enrichment and sequestration of the vector.
The core events in initial process of inflammation are vascular response and leukopedesis. Molecules involved within the process of leukocyte capture, adhesion and rolling have been widely investigated to enhance vector targeting including selectins, integrins, cellular adhesion molecules (CAMs) etc.. As inflammation is a complex, multi-signal process, only carriers with pleiotropic properties will have desirable application prospects. Familiarity with the common action mechanism of existing carriers is a prerequisite for the more reasonable design of future carrier. Qin and Yu comprehensively summarized the action mechanism of inflammation-oriented vectors comprising the halt of inflammation progression by blockage of inflammatory mediators, increased nanoparticles accumulation at inflamed tissues utilizing inflammatory signal, and prolonged systemic circulation through inhibition of systemic clearance.
To provide specific and practical guidance for researchers to construct and evaluate inflammation targeting vectors rationally, this review also introduces the nanoparticle classification based on targeting moiety category, methods to combine targeting moiety with core nanoparticles, as well as techniques for assessing targetability in vitro and in vivo. The drug delivery systems targeting inflammation can be divided into two categories: passive targeting and active targeting. The passive targeting vectors were albumin-based nanoparticles and lipoprotein mimetic nanotherapeutics, which utilizing the recognition by their natural receptors expressed in phagocytes. To attain active targeting effect of the vectors, various targeting modalities can be adopted comprising protein/protein domain/peptide to mimic the interaction region, recognition using antibodies, camouflage of cellular membrane, natural ligands of inflammatory receptors as well as nanoparticles as hitchhiker on inflammatory cells. To modify the vector with ligands, both covalent coupling and non-covalent coupling were used. To conjugate the vector with inflammatory cells, electrostatic adsorption and covalent coupling were usually exploited. And endocytosis of the vector was often used to prepare inflammatory cells similar to Trojan horses.
Targeting evaluation in vitro is always meaningful in prescription optimization, which is faster, more economic and easier in batch screening. Related methods include internalization of the nanoparticles by inflammatory cells, transwell assay, dynamic flow chamber, surface plasmon resonance, together with quartz crystal microbalance with dissipation monitoring etc. Although exquisitely designed in vitro assays attempt to simulate physiological or pathological microenvironment, the complicated internal milieu and dynamic change characteristics under inflammation state make it indispensable for the in vivo assay using animal model to accurately evaluate the performance of vectors. With help of many advanced techniques, spatiotemporal biodistribution of the vectors have been qualitatively and quantitatively rated after administration using fluorescence imaging, magnetic resonance imaging and scintigraphy based on radionuclide, which provided practical basis for further optimization of the vectors.
Despite significant achievements in nanotechnology in the past decade, the vast majority of research on drug-loaded nanoparticles for the treatment of inflammatory diseases has only remained at the preclinical stage. At present, no biomimetic nanoparticle targeting inflammation has entered clinical-stage development. This will be highly anticipated that with innovation of nanotechnology platforms, consummation of safety evaluation system for nanocarriers, and improvement in pilot production, nanoparticle drug delivery systems for anti-inflammatory drugs may finally enter clinical study, thus opening a new chapter for inflammation diagnosis and treatment.
